Effects of Allergic Inflammation on TLR2 Signaling and Mycoplasma Infection

过敏性炎症对 TLR2 信号传导和支原体感染的影响

• 批准号: 8122225
• 负责人: Hong W Chu
• 金额: $ 38.61万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122225
• 关键词: Acute; Adoptive Transfer; Affect; Allergic; Allergic inflammation; Asthma; Attenuated; Automobile Driving; Bacteria; Bacterial Infections; Bone Marrow; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Chronic; Collagen; Dendritic Cells; Deposition; Dose; Epithelial Cells; Host Defense; Human; Immune response; Immunologics; In Vitro; Infection; Interleukin-12; Interleukin-13; Interleukin-4; Knowledge; Ligands; Lung; Lung diseases; Molecular; Mucins; Mus; Mycoplasma Infections; Mycoplasma pneumonia infection; Mycoplasma pneumoniae; NF-kappa B; Natural Immunity; Pathway interactions; Phenotype; Physiologic pulse; Predisposition; Process; Production; Research; Research Proposals; Role; STAT6 Transcription Factor; Signal Pathway; Signal Transduction; Testing; Therapeutic; Toll-Like Receptor 2; airway remodeling; allergic response; antimicrobial; cytokine; design; in vivo; mast cell; mouse model; novel; novel therapeutics; pathogen; respiratory; response; Acute; Adoptive Transfer; Affect; Allergic; Allergic inflammation; Asthma; Attenuated; Automobile Driving; Bacteria; Bacterial Infections; Bone Marrow; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Chronic; Collagen; Dendritic Cells; Deposition; Dose; Epithelial Cells; Host Defense; Human; Immune response; Immunologics; In Vitro; Infection; Interleukin-12; Interleukin-13; Interleukin-4; Knowledge; Ligands; Lung; Lung diseases; Molecular; Mucins; Mus; Mycoplasma Infections; Mycoplasma pneumonia infection; Mycoplasma pneumoniae; NF-kappa B; Natural Immunity; Pathway interactions; Phenotype; Physiologic pulse; Predisposition; Process; Production; Research; Research Proposals; Role; STAT6 Transcription Factor; Signal Pathway; Signal Transduction; Testing; Therapeutic; Toll-Like Receptor 2; airway remodeling; allergic response; antimicrobial; cytokine; design; in vivo; mast cell; mouse model; novel; novel therapeutics; pathogen; respiratory; response

DESCRIPTION (provided by applicant): Airway infection, such as atypical bacterium Mycoplasma pneumoniae (Mp), contributes to asthma pathobiology. One key unanswered question is: What are the lung immunologic and molecular mechanisms by which asthmatics are susceptible to bacterial infections? Specifically, does an established allergic airway milieu in asthmatics enhance host susceptibility to Mp infection? Our previous studies in mouse models and human primary airway epithelial cell cultures have demonstrated that: 1) Mp activates Toll-like receptor 2 (TLR2) signaling pathway in mouse lungs including airway epithelial cells and dendritic cells (DCs), and human primary bronchial epithelial cells; 2) TLR2 activation is critical for host defense against Mp infection through induction of Th1 response and antimicrobial substances; 3) Allergic inflammation and/or Th2 cytokines reduce TLR2 activation, leading to an impaired lung Mp clearance (or a persistent low level of Mp); 4) TLR2 activation using Pam3CSK4 (a TLR2 ligand) or neutralizing IL-4 and IL-13 in allergic mice restore the impaired Mp clearance; and 5) In an established allergic milieu, Mp infection, particularly at a low dose, increases Th2 differentiation. Our preliminary studies led us to hypothesize that an established allergic airway milieu down-regulates innate immunity (i.e., TLR2 activation), predisposes the host to a persistent low level of Mp infection, and consequently leads to an increased allergic airway response. To test this central hypothesis, we have proposed three specific aims. Aim 1 is to test the hypothesis that an established allergic airway milieu reduces TLR2 activation in Mp-infected mice, leading to a persistent low level of lung Mp. TLR2 activation (use of TLR2 ligand Pam3CSK4 or adoptive DC transfer) prior to the establishment of allergic inflammation will restore the impaired Mp clearance in allergic lungs by promoting the Th1 response. Aim 2 is to test the hypothesis that upon Mp infection, Th2 cytokines (IL-4, IL-13) inhibit TLR2 activation of airway epithelial cells (less TLR2 and antimicrobial substances) and lung DCs (less TLR2 and Th1-driving cytokine [e.g., IL-12] production). IL-4 and IL-13 inhibit Mp-induced TLR2 activation through suppressing NF-?B activity via signal transducer and activator of transcription 6 (STAT6) signaling pathway. Aim 3 is to test the hypothesis that in contrast to higher doses, lower doses of Mp in an allergic milieu enhance allergic responses. Lower doses of Mp fail to induce TLR2 activation in Th2 cytokine-exposed DCs, leading to a DC phenotype (e.g., increased Jagged1 expression) in favor of Th2 differentiation of naive CD4+ T cells. Our proposed studies will reveal novel molecular mechanisms involved in an increased susceptibility of asthmatics to bacterial infections, which will provide the basic information in the design of therapeutic strategies to attenuate airway infectious and allergic processes in asthma. Project Narrative: Our research findings will significantly advance our knowledge with regard to the mechanisms of an increased susceptibility of asthmatics to bacterial infections, thus helping the design of novel therapeutic strategies in attenuating airway infectious and allergic processes in asthma and perhaps other chronic pulmonary diseases.

描述（由申请人提供）：气道感染，例如非典型细菌支原体肺炎（MP），有助于哮喘病理生物学。一个关键的未解决的问题是：哮喘患者容易受到细菌感染的肺部免疫和分子机制是什么？具体而言，哮喘患者中已建立的过敏性气道环境是否可以增强宿主对MP感染的敏感性？我们先前在小鼠模型和人类原代气道上皮细胞培养物中的研究表明：1）MP在包括气道上皮细胞和树突状细胞（DCS）的小鼠肺中激活类似Toll样受体2（TLR2）信号通路，以及人类原发性支气管上皮细胞； 2）TLR2激活对于通过诱导Th1反应和抗菌物质来防御MP感染至关重要。 3）过敏性炎症和/或Th2细胞因子降低TLR2激活，从而导致肺MP清除受损（或MP持续的低水平）； 4）使用PAM3CSK4（TLR2配体）或中和IL-4和IL-13的TLR2激活在过敏小鼠中恢复了受损的MP清除率； 5）在已建立的过敏环境中，MP感染，尤其是在低剂量下，会增加Th2分化。我们的初步研究使我们假设已建立的过敏性气道环境下调了先天免疫力（即TLR2激活），使宿主持续到持续的MP感染水平持续低，因此导致了增加的过敏性气道反应。为了检验这一中心假设，我们提出了三个具体目标。目的1是检验以下假设：已建立的过敏性气道环境减少了MP感染小鼠的TLR2激活，从而导致持续的低水平肺MP。在建立过敏性炎症之前，TLR2激活（使用TLR2配体PAM3CSK4或收养DC转移）通过促进TH1反应来恢复过敏肺中的MP清除率受损。 AIM 2是测试以下假设：在MP感染后，Th2细胞因子（IL-4，IL-13）抑制了气道上皮细胞（较少的TLR2和抗菌物质）和肺DC的TLR2激活（较少的TLR2和抗菌物质）（TLR2和TLR2和Th1-Driving driving driving driving cytokine [E.G.，IL-12]生产）。 IL-4和IL-13通过通过信号换能器和转录6（STAT6）信号通路抑制NF-？B活性来抑制MP诱导的TLR2激活。目的3是检验以下假设：与较高剂量相比，过敏环境中的MP较低剂量增强了过敏反应。较低剂量的MP无法在Th2细胞因子暴露的DC中诱导TLR2激活，从而导致DC表型（例如，锯齿状1表达增加），有利于幼稚CD4+ T细胞的Th2分化。我们提出的研究将揭示哮喘患者对细菌感染的敏感性增加的新型分子机制，这将在设计治疗策略中提供基本信息，以减轻哮喘中气道传染和过敏过程。项目叙述：我们的研究发现将大大提高我们对哮喘患者对细菌感染的敏感性增加的机制的了解，从而有助于设计新型治疗策略，以减轻哮喘和其他慢性肺部疾病的气道感染性和过敏性过程。